1. Field of the Invention
The present invention relates generally to the field of therapeutic treatment and compounds having utility therefor, in particular the therapy or management of conditions associated with excessive, unwanted or undesirable sodium ion passage through cellular membranes via voltage-gated sodium channels. In one embodiment the invention is concerned with the treatment of neuropathic pain. The invention contemplates to aryloxy-substituted amines, as sodium channel blockers or modulators. In further embodiments, the invention also relates to compounds which may advantageously have dual sodium channel blocker/modulating and antioxidative (free-radical scavenging) effects. Methods for their manufacture and compositions containing the compounds are also contemplated.
2. Description of the Prior Art
The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.
The electrical potential difference across a neuronal cell membrane is the result of an inequitable distribution of ions on either side of the membrane. In its resting state, a neuron has a high internal store of potassium ions (K+) with sodium ions (Na+) accumulated on the outside of the membrane. In such a state, the flow of ions across a membrane is such that their movement causes no net change in charge. However, a perturbation of this resting flow results in an alteration of the membrane's potential.
Sodium channels are aqueous pores in the cellular membrane which regulate and provide a selective passage for sodium ions between the internal and external environments of a cell. Voltage-gated sodium channels, ie. those opened by changes in membrane potential, are largely responsible for the depolarization of the cell. When closed, they help maintain the neuron's resting potential, and when open, allow sodium ions to flow down the electrochemical gradient and depolarize the cell.
The voltage-gated sodium channel is formed by proteins embedded within the cell's membrane and has three known subunits: a large glycoprotein called the α-subunit, which probably forms the channel's pore, and two smaller polypeptides called γ1 and β2 which regulate the function of the α-subunit. γ- and δ-Subunits may also exist to regulate the α-subunit.
The α-subunit has four repeats, labelled I through IV, of the same 150 amino acid sequence. Each repeat contains six membrane-spanning regions labelled S1 through S6. The highly conserved S4 region, thought to be part of the channel that acts as its voltage sensor, has a positive amino acid at every third position, with hydrophobic residues between these. It is thought that when stimulated by a change in transmembrane voltage, this subunit moves from within the pore toward the extracellular side of the cell, allowing the channel to become permeable to ions which would otherwise have been blocked by the subunit's positive charges.
Voltage-gated sodium channels can have three states: resting (closed), activated (open), and inactivated (closed). Channels in the resting state are blocked on their intracellular side by an “activation gate” which is removed in response to stimulation that opens the channel. The ability to inactivate is thought to be due to a tethered plug (formed by domains III and IV of the alpha subunit), called an inactivation gate, that blocks the inside of the channel shortly after it has been activated. During an action potential the channel remains inactivated for a few milliseconds after the neuron is finished depolarizing. The inactivation is removed when the membrane potential of the neuron becomes negative after the falling phase of the action potential. This allows the channels to be activated again during the next action potential.
The inner pore of sodium channels contains a selectivity filter made of negatively charged amino acid residues (aspartic acid and glutamic acid), which attract the positive Na+ ion and keep out negatively charged ions such as chloride. The mouth of the pore is some 1.2 nm wide, narrowing to about 0.3 by 0.5 nm wide, which is just large enough to allow a single Na+ ion with a water molecule associated to pass through whilst being small enough to exclude larger K+ ions. Differently sized ions also cannot interact as well with the negatively charged glutamic acid residues that line the pore. Voltage-gated sodium channels are further characterised with regard to their voltage dependence and kinetic behaviour.
Opening of Na+ channels in response to an electrical stimulus results in a rapid influx of sodium ions. This causes a small localised disturbance in the membrane potential which open voltage-gated Na+ channels in adjacent areas of the membrane, where in turn, the membrane's electrical potential changes as ions flow across. After the excitatory stimulus, the Na+ channels close and the membrane potential is restored to its resting value by an outflow of potassium ions.
Thus, changes in membrane potential are propagated along the membrane from the point of stimulation. A self-propagating wave of depolarization down the axon of a neuron is known as an action potential. The more Na+ channels which exist in a neuron's membrane, the faster the action potential will propagate down the axon. When it reaches the end of the axon, the action potential may electrically stimulate the membrane of an adjacent cell or release neurotransmitters into the synaptic cleft, which chemically open gated channels in the adjacent cell membrane. Voltage-gated sodium channels thus play a prominent and significant role in action potentials and, ultimately, the electrical activity of the central and peripheral nervous systems.
Notwithstanding the essential role of voltage-gated sodium channels in the central and peripheral nervous systems, it is now well established that they also implicated in the aetiology of a number of neuronal diseases and conditions (neuropathies). Depending on the particular nerves involved, the neuropathy can be classified as a central or peripheral neuropathy. Central neuropathies arise from spinal cord, brainstem, thalamic, and cerebral damage or disease, while peripheral neuropathies arise from damage or disease of peripheral nerves.
The peripheral nervous system transmits information from the brain and spinal cord to every other part of the body. More than 100 types of peripheral neuropathy have been identified, each with its own characteristic set of symptoms, pattern of development, and prognosis. Impaired function and symptoms depend on the type of nerves—motor, sensory, or autonomic—that are damaged. Some people may experience temporary numbness, tingling, and pricking sensations, sensitivity to touch, or muscle weakness. Others may suffer more extreme symptoms, including burning pain (especially at night), muscle wasting, paralysis, or organ or gland dysfunction. Peripheral neuropathy may be either inherited or acquired. Causes of acquired peripheral neuropathy include systemic diseases (e.g. diabetes), physical injury (trauma) to a nerve, tumors, toxins, autoimmune responses, viral and bacterial infections, nutritional deficiencies, alcoholism, and vascular and metabolic disorders. Inherited forms of peripheral neuropathy are caused by genetic mutations.
Central neuropathy, as the name implies, is the result of damage to the central nervous system, i.e. brain and spinal cord. As with peripheral neuropathies, the causes are varied and include physical injury, disease and autoimmune responses.
A particular example of such a neuropathy is multiple sclerosis (MS) which is a chronic, often disabling, disease that randomly attacks the central nervous system. The progress, severity and specific symptoms of the disease cannot be predicted; symptoms may range from tingling and numbness to paralysis and blindness. MS is a devastating disease because people live with its unpredictable physical and emotional effects for the rest of their lives. Symptoms of MS are unpredictable and vary greatly from person to person and from time to time in the same person. They may include: fatigue, impaired vision, loss of balance and muscle coordination, slurred speech, tremors, stiffness, bladder and bowel problems, difficulty walking, short-term memory loss, mood swings and, in severe cases, partial or complete paralysis.
A significant contributor to non-remitting deficits in demyelinating neuroinflammatory diseases such as MS and the related Guillain-Barre's syndrome (GBS), and their respective animal models, experimental allergic encephalomyelitis (EAE) and experimental autoimmune neuritis (EAN), is axonal loss. Recent studies have demonstrated that persistently activated sodium channels can trigger axonal injury by providing a sustained sodium influx that can drive reverse sodium-calcium exchange (Stys et al., 1992b, 1993; Craner et al., 2004) and sodium channel blockade can prevent axonal degeneration within white matter tracts in a variety of disease models (Stys et al., 1992a,b; Rosenberg et al., 1999; Kapoor et al., 2003; Lo et al., 2003; Bechtold et al., 2004). In addition, it has recently been demonstrated that the sodium channel blocker phenyloin inhibits immune cells in the neuroinflammatory disorders (Craner et al., 2005), and that administration of the sodium channel blocker flecainide in the EAN model, significantly increased the number of functional axons and significantly decreased axonal loss (Bechtold et al., 2005).
Physical trauma (car accident, gunshot, falls, etc.) or disease (polio, spina bifida, Friedreich's Ataxia, etc.) can lead to spinal cord injury (SCI)— damage to the spinal cord that results in a loss of function such as mobility or feeling. The spinal cord does not have to be severed in order for a loss of functioning to occur. In fact, in most people with SCI, the spinal cord is intact, but the damage to it results in loss of functioning. The extent of loss of function will vary depending on the area of injury but can range from quadriplegia, partial loss of function or dexterity in the arms and hands, paraplegia, poor trunk control as the result of lack of abdominal muscle control reduced control of the hip flexors and legs. Besides a loss of sensation or motor functioning, individuals with SCI also experience other changes. For example, they may experience dysfunction of the bowel and bladder. Very high injuries (C-1, C-2) can result in a loss of many involuntary functions including the ability to breathe, necessitating breathing aids such as mechanical ventilators or diaphragmatic pacemakers. Other effects of SCI may include low blood pressure, inability to regulate blood pressure effectively, reduced control of body temperature, inability to sweat below the level of injury, and chronic pain.
Secondary cell injury due to spinal cord trauma results, in part, from the accumulation of calcium ions within injured neurons and their axons. As noted above, this arises due to reverse operation of the sodium-calcium exchanger, which in turn is triggered by an increase in intracellular sodium concentration via persistently activated voltage-gated sodium channels. Pharmacological blockade of sodium channels has been shown to prevent axonal degeneration and preserve function after injury to central nervous system white matter tracts. Sodium channel blockade with tetrodotoxin (TTX), and tertiary and quaternary amine local anaesthetics have been shown to prevent the development of irreversible dysfunction of axons within the anoxic optic nerve (Stys et al., 1992a,b) and spinal cord (Imaizumi et al., 1997) in vitro. TTX applied focally after contusion spinal cord injury (SCI) reduces axoplasmic pathology and damage to myelin, results in residual white matter sparing, and enhances behavioral recovery (Rosenberg et al., 1999; Teng and Wrathall, 1997). Systemic lidocaine after compression SCI results in improved recovery of somatosensory-evoked responses (Kobrine et al., 1984). A charged derivative of lidocaine, QX-314, given after compression SCI partially preserves descending motor axons (Agrawal and Fehlings, 1997). In vitro studies have demonstrated that phenyloin, a drug that blocks sodium channels and inhibits persistent sodium currents (Chao and Alzheimer, 1995; Segal and Douglas, 1997), has a protective effect on axons within white matter after anoxia (Fern et al., 1993). Phenyloin given after compression SCI results in less tissue loss at the injury epicenter, but in these animals, measures of motor function were reported to be poorer (Schwartz and Fehlings, 2001). Phenyloin has recently been shown to protect against axonal degeneration of spinal cord axons and improve neurological outcome in mice with experimental allergic encephalomyelitis (Lo et al., 2002, 2003). The sodium channel blocker flecainide has a similar protective effect (Bechtold et al., 2004). It was subsequently shown that treatment with phenytoin after SCI confers substantial neuroprotection, with sparing of both white and grey matter surrounding the impact site, exerts a protective effect on axons, reduces loss of action potential conduction along spinal cord axons through the impact site and promotes locomotor recovery (Hams et al., 2004).
Many peripheral or central neuropathic conditions commonly result in pain. Pain can be classed as acute (or nociceptive) or neuropathic.
Nociceptive pain is mediated by thermal, mechanical, electrical or chemical stimulation of pain receptors, known as nociceptors, which are located in skin, bone, connective tissue, muscle and viscera. Its purpose is to serve as a protective biological warning of potential ongoing tissue damage and is experienced in and around the point of injury. It usually responds to opioid and/or Non Steroidal Anti-Inflammatory (NSAID) treatment. In the main, as healing progresses, the pain and inflammation associated with an injury abates and resolves.
In contrast, individuals may experience pain in the absence of an obvious tissue injury, or suffer chronic or protracted pain long after the injured tissue is apparently healed. Such pain serves no protective biological function and is predominantly neuropathic in nature, thus referred to as neuropathic pain. Neuropathic pain has been variously described as pain that results from a pathologic change in nerves or pain initiated or caused by a primary lesion or dysfunction in the nervous system (Mersky and Bogduk, 1994; De Andres and Garcia-Ribas, 2003) and can be described as burning, electric, tingling and shooting in nature. Neuropathic pain is associated with a variety of disease states and presents in the clinic with a wide range of symptoms. (Woolf and Mannion, 1999). The damage to the nerves may be caused by accidental or surgical injury, by metabolic disturbances such as diabetes or vitamin B12 or other nutrient deficiency, by ischaemia, by radiation, by autoimmune attack, by cytotoxic drugs used in cancer chemotherapy, by alcohol, by infections, especially viral infections, particularly with the herpes virus, by tumours, by degenerative diseases, or by unknown factors such as may be operative in trigeminal and other neuralgias. Neuropathic pain does not require specific pain receptor stimulation although such stimulation can add to the intensity of the pain sensation (Baron, 2003).
Neuropathic pain is often characterised by chronic allodynia and/or hyperalgesia. Allodynia is pain resulting from a non-noxious stimulus, ie a stimulus that does not ordinarily cause a painful response, eg a light touch. Hyperalgesia, on the other hand, is an increased sensitivity to noxious stimuli (injury), ie a greater than normal pain response, and can be further defined as primary, occurring immediately in the vicinity of an injury, or secondary, occurring in undamaged area remote from an injury. Neuropathic pain is usually unresponsive to treatments used for nociceptive pain.
It is estimated that neuropathic pain affects over 26 million people worldwide (Butera 2007) and despite its common occurrence, neuropathic pain remains one of the most poorly understood and untreated conditions in primary care and can have a debilitating effect on almost all aspects of a sufferer's life. It has been associated with depression, anxiety, loss of independence and can impact on an individual's relationships and ability to work. The annual cost of neuropathic pain in the United States alone, including medical expenses, lost income and lost productivity is estimated to be $100 billion. The condition is particularly prevalent amongst the elderly and is experienced by a significant proportion of patients suffering from other disease states such as diabetes and advanced cancer.
Sodium channel blockers have been reported as useful agents in the treatment of neuropathic pain (Tanelian et al, 1995; Kyle and Ilyin, 2007). There is evidence that sodium channel blockers selectively suppress etopic neural firing in injured (unmyelinated) nerves, which have an accumulation of sodium channels, and studies carried out on known blockers, such as carbamazepine, phenyloin, lidocaine and mexiletine, have demonstrated utility in the treatment of various types of neuropathic pain. Consistent with this, is the demonstration that sodium channels accumulate in the peripheral nerve sites of axonal injury (Devor et al, 1993) and also in second order sensory neurons in pain pathways in the spinal cord (Hams et al, 2004 b). Alterations in the either the level of expression or distribution of sodium channels within an injured nerve, therefore, have a major influence on the pathophysiology of pain associated with this type of trauma.
Given the individual and social impact of the central and peripheral nervous system disease states, including neuropathic pain, and conditions in which excessive, undesirable or otherwise unwanted sodium channel activity is involved or implicated, there remains the need for new compounds, which may act as sodium channel inhibitors or modulators to ameliorate, relieve, prevent or otherwise improve one or more of their symptoms, or the conditions themselves.